pH-temperature Responsive Hydrogel-Mediated Delivery of Exendin-4 Encapsulated Chitosan Nanospheres for Sustained Therapeutic Efficacy in Type 2 Diabetes Mellitus.

Type 2 Diabetes Mellitus (T2D) is a chronic, obesity-related, and inflammatory disorder characterize by insulin resistance, inadequate insulin secretion, hyperglycemia, and excessive glucagon secretion. Exendin-4 (EX), a clinically established antidiabetic medication that acts as a glucagon-like peptide-1 receptor agonist, is effective in lowering glucose levels and stimulating insulin secretion while significantly reducing hunger. However, the requirement for multiple daily injections due to EX's short half-life is a significant limitation in its clinical application, leading to high treatment costs and patient inconvenience. To address this issue, an injectable hydrogel system is developed that can provide sustained EX release at the injection site, reducing the need for daily injections. In this study, the electrospray technique is examine to form EX@CS nanospheres by electrostatic interaction between cationic chitosan (CS) and negatively charged EX. These nanospheres are uniformly dispersed in a pH-temperature responsive pentablock copolymer, which forms micelles and undergoes sol-to-gel transition at physiological conditions. Following injection, the hydrogel gradually degraded, exhibiting excellent biocompatibility. The EX@CS nanospheres are subsequently released, maintaining therapeutic levels for over 72 h compared to free EX solution. The findings demonstrate that the pH-temperature responsive hydrogel system containing EX@CS nanospheres can be a promising platform for the treatment of T2D.

MMPP promotes adipogenesis and glucose uptake via binding to the PPARγ ligand binding domain in 3T3-L1 MBX cells.

Peroxisome proliferator-activated receptor-gamma (PPARγ) is a transcription factor involved in adipogenesis, and its transcriptional activity depends on its ligands. Thiazolidinediones (TZDs), well-known PPARγ agonists, are drugs that improve insulin resistance in type 2 diabetes. However, TZDs are associated with severe adverse effects. As current therapies are not well designed, novel PPARγ agonists have been investigated in adipocytes. (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP) is known to have anti-arthritic, anti-inflammatory, and anti-cancer effects. In this study, we demonstrated the adipogenic effects of MMPP on the regulation of PPARγ transcriptional activity during adipocyte differentiation in vitro. MMPP treatment increased PPARγ transcriptional activity, and molecular docking studies revealed that MMPP binds directly to the PPARγ ligand binding domain. MMPP and rosiglitazone showed similar binding affinities to the PPARγ. MMPP significantly promoted lipid accumulation in adipocyte cells and increased the expression of C/EBPß and the levels of p-AKT, p-GSK3, and p-AMPKα at an early stage. MMPP enhanced the expression of adipogenic markers such as PPARγ, C/EBPα, FAS, ACC, GLUT4, FABP4 and adiponectin in the late stage. MMPP also improved insulin sensitivity by increasing glucose uptake. Thus, MMPP, as a PPARγ agonist, may be a potential drug for type 2 diabetes and metabolic disorders, which may help increase adipogenesis and insulin sensitivity.

Use of real-world evidence data to evaluate the comparative effectiveness of second-line type 2 diabetes medications on chronic kidney disease.

Chronic kidney disease (CKD) is a common complication of type 2 diabetes mellitus (T2DM). Approximately-one-third of patients with T2DM also have CKD. In clinical trial studies, several anti-diabetic medications (ADM) show evidence of preventing the progression of CKD. Biguanides (e.g., metformin) are widely accepted as the first line medication. However, the comparative effectiveness of second line ADMs on CKD outcomes in T2DM is unclear. In addition, results from clinical trials may not generalize into routine clinical practice. In this study, we aimed to investigate the association of second line ADMs with diagnosed incident CKD, CKD hospitalization, and eGFR < 45 mL/min in T2DM patients using real-world data from electronic health records. Our study found that treatment with sodium-glucose cotransporter 2 (SGLT-2) inhibitors was significantly associated with lower risk of diagnosed CKD incidence in both primary analysis (hazard ratio, 0.43; 95 % CI, [0.22;0.87]; p-value,0.02) and secondary analysis (hazard ratio, 0.42; 95 % CI, [0.19;0.92]; p-value, 0.03) compared to use of Sulfonylureas (SU) as a second-line ADM. However, significant associations were not observed when using eGFR < 45 mL/min as the endpoint. Treatment with a dipeptidyl peptidase 4 (DPP-4) inhibitor was significantly associated with lower risk of diagnosed incident CKD (hazard ratio, 0.7; 95 % CI, [0.53;0.96]; p-value, 0.03) and lower risk of CKD hospitalization (hazard ratio, 0.6; 95 % CI, [0.37; 0.96]; p-value, 0.04) in the primary analysis. However, both associations were not significant in the sensitivity analysis. We did not observe significant association between use of glucagon-like peptide 1 receptor agonists (GLP-1RA), Thiazolidinediones (TZD), insulin and diagnosed CKD incidence, hospitalization or eGFR < 45 mL/min compared to use of SU as a second-line ADM.

Oral GLP1 Gene Delivery by an Antibody-Guided Nanomaterial to Treat Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is a chronic and progressive hyperglycemic condition. Glucagon-like peptide-1 (GLP1) is an incretin secreted from pancreatic ß-cells and helps to produce insulin to balance the blood glucose level without the risk of hypoglycemia. However, the therapeutic application of GLP1 is limited by its intrinsic short half-life and rapid metabolic clearance in the body. To enhance the antidiabetic effect of GLP1, we designed a human cysteine-modified IgG1-Fc antibody-mediated oral gene delivery vehicle, which helps to produce GLP1 sustainably in the target site with the help of increased half-life of the Fc-conjugated nanocarrier, protects GLP1 from acidic and enzymatic degradation in the gastrointestinal (GI) tract, uptakes and transports the GLP1 formulation through the neonatal Fc receptor (FcRn), and helps to release the GLP1 gene in the intestine. Our formulation could reduce the blood glucose from about an average of 320 mg/dL (hyperglycemic) to 150 mg/dL (normal blood glucose concentration) in diabetic mice, which is about 50% reduction of the total blood glucose concentration. GLP1 (500 µg) complexed with the IgG1-Fc carrier was proven to be the optimal dose for a complete reduction of hyperglycemic conditions in diabetic mice. A significant amount of insulin production and the presence of GLP1 peptide were observed in the pancreatic islets of oral GLP1 formulation-treated diabetic mice in immunohistochemistry analysis compared to nontreated diabetic mice. The orally given formulation was completely nontoxic according to the histopathology analysis of mice organ tissues, and no mice death was observed. Our antibody-mediated oral gene delivery system is a promising tool for various oral therapeutic gene delivery applications to treat diseases like diabetes.

Efficacy and safety of evogliptin in the treatment of type 2 diabetes mellitus in a Brazilian population: a randomized bridging study.

BACKGROUND: Evogliptin (EVO) is a potent and selective dipeptidyl peptidase-4 inhibitor (DPP4i) developed for the treatment of type 2 diabetes mellitus (T2DM). DPP4is are known to exhibit a better glucose-lowering effect in Asians compared to other ethnic groups. Once EVO's clinical development program was conducted in Asian patients, this bridging study was designed to validate for the Brazilian population the efficacy and safety of the approved dose regimen (once-daily 5.0 mg). METHODS: In this randomized, double-blind, double-dummy, parallel trial, 146 patients with T2DM with inadequate glycemic control on diet and exercise (7.5% ≤ HbA1c ≤ 10.5%) were randomly assigned to a 12-week once-daily treatment with EVO 2.5 mg (N = 35), EVO 5 mg (N = 36), EVO 10 mg (N = 36), or sitagliptin (SITA) 100 mg (N = 39). Absolute changes (Week 12-baseline) in HbA1c, fasting plasma glucose (FPG) and body weight (BW) were obtained. One-sided one sample t test was used to determine if mean HbA1c reduction in each group was < - 0.5% (beneficial metabolic response). An analysis of covariance estimated the change in HbA1c and FPG adjusted by baseline HbA1c, FPG, body mass index (BMI) and study site. Response rates to treatment were also established. No between-group statistical comparisons were planned. RESULTS: HbA1c mean reductions were - 1.26% (90% CI - 1.7%, - 0.8%), - 1.12% (90% CI - 1.4%, - 0.8%), - 1.29% (90% CI - 1.6%, - 1.0%), and - 1.15% (90% CI - 1.5%, - 0.8%) in groups EVO 2.5 mg, EVO 5 mg, EVO 10 mg, and SITA 100 mg, respectively. FPG levels showed a mean increase of 10.89 mg/dL in group EVO 2.5 mg, with significant mean reductions of - 18.94 mg/dL, - 21.17 mg/dL, and - 39.90 mg/dL in those treated with EVO 5 mg, EVO 10 mg, and SITA 100 mg, respectively. BW showed significant reductions of approximately 1 kg in patients treated with EVO 5 mg, EVO 10 mg, and SITA 100 mg. Mean adjusted reductions of HbA1c and FPG levels confirmed the significant clinical benefit of all study treatments. The clinical benefit of EVO's "target" dose (5 mg) was confirmed. No safety concerns were identified. CONCLUSIONS: These results validate for the Brazilian population the approved dose regimen of EVO (once-daily 5 mg).Trial registration ClinicalTrials.gov Identifier: NCT02689362 (first posted on 02/23/2016).

Cardiovascular Protection in the Treatment of Type 2 Diabetes: A Review of Clinical Trial Results Across Drug Classes.

Patients with type 2 diabetes (T2DM) have a significantly higher risk of developing cardiovascular disease (CVD)-namely myocardial infarction, heart failure, and stroke. Despite clear advances in the prevention and treatment of CVD, the impact of T2DM on CVD outcome remains high and continues to escalate. Available evidence indicates that the risk of macrovascular complications increases with the severity of hyperglycemia, thus suggesting that the relation between metabolic disturbances and vascular damage is approximately linear. Although current antidiabetic drugs are highly effective for the management of hyperglycemia, most T2DM patients remain exposed to a substantial and concrete risk of CVD. Over the last decade many glucose-lowering agents have been tested for their safety and efficacy in T2DM with CVD. Noteworthy, most of these studies failed to show a significant benefit in terms of CV morbidity and mortality, despite intensive glycemic control. The recent trials Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME); Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6); Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER); and Insulin Resistance Intervention After Stroke (IRIS) have shed some light on this important clinical issue, thus showing a convincing effect of empagliflozin, liraglutide, and pioglitazone on CVD outcomes. Here we provide a critical and updated overview of the main glucose-lowering agents and their risk/benefit ratio for the prevention of CVD in patients with T2DM.

Percepção do idoso diabético sobre o papel da família no tratamento / Perception of elderly patients with diabetes about the role of the family in the treatment / Percepción del anciano diabético sobre el papel de la familia en el tratamiento

O objetivo da pesquisa foi conhecer a percepção dos idosos diabéticos acerca da participação da família em seu tratamento. Participaram seis idosos que responderam a uma entrevista semiestruturada. Constataram-se maiores dificuldades em relação à adesão alimentar e ao exercício físico. Foi observada a importância do envolvimento familiar no alcance do controle glicêmico e na qualidade de vida dos entrevistados, e que a família necessita ser apoiada para que consiga desempenhar o papel de diligente.

The objective was to know the perception of elderly diabetics about family participation in treatment. Participants were six elderly who answered a semi-structured interview. It found major difficulties in relation to food and exercise adherence. It was observed the importance of family involvement in achieving glycemic control and quality of life of respondents and that the family needs to be supported so you can play the role of diligent.

El objetivo de la investigación fue conocer la percepción de los ancianos diabéticos acerca de la participación de la familia en su tratamiento. Participaron seis ancianos que respondieron a una entrevista semiestructurada. Se constataron mayores dificultades en relación a la adhesión alimenticia y al ejercicio físico. Se observó la importancia de la participación familiar en el alcance del control glucémico y en la calidad de vida de los entrevistados y que la familia necesita ser apoyada para que pueda desempeñar el papel de diligente.

The combination of DPP-4 inhibitors versus sulfonylureas with metformin after failure of first-line treatment in the risk for major cardiovascular events and death.

OBJECTIVE: To determine whether the combination of dipeptidyl-peptidase 4 (DPP-4) inhibitors vs. sulfonylureas with metformin after failure of first-line treatment is associated with a decreased risk for major adverse cardiovascular events (myocardial infarction and stroke) and for all-cause mortality. METHOD: Using the UK Clinical Practice Research Datalink, a cohort of patients newly treated with metformin or sulfonylurea monotherapy between January 1, 1988, and December 31, 2011, was identified and was followed until December 31, 2012. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models to compare the DPP-4 inhibitor-metformin combination to the sulfonylurea-metformin combination so as to study the risk for a composite endpoint consisting of myocardial infarction, stroke and all-cause mortality. The models were adjusted for high-dimensional propensity score deciles. RESULTS: The cohort consisted of 11,807 patients that included 2286 on a DPP-4 inhibitor-metformin combination and 9521 on a sulfonylurea-metformin combination. The crude incidence rates (95% CIs) of the composite endpoint were 1.2% (0.8% to 1.7%) and 2.2% (1.9% to 2.5%) per year for the DPP-4 inhibitor-metformin and sulfonylurea-metformin combinations, respectively. In the high-dimensional propensity score-adjusted model, the use of the DPP-4 inhibitor-metformin combination was associated with a 38% decreased risk for the composite endpoint (adjusted HR: 0.62; 95% CI 0.40 to 0.98), compared with the sulfonylurea-metformin combination. CONCLUSIONS: The use of a DPP-4 inhibitor combination with metformin, compared with a sulfonylurea-metformin combination, was associated with decreased risks for major cardiovascular events and all-cause mortality.

Self-monitoring of blood glucose: use, frequency drivers, and cost in Argentina.

Although test strips for self-monitoring of blood glucose (SMBG) represent around 50% of diabetes treatment cost in Argentina, little is known about their current use and relationship with different types of treatment. We therefore aimed to estimate the current use of test strips and identify the major use drivers and the percentage they represent of total prescription costs in 2 entities of the social security system (SSS) of Argentina. Observational retrospective study measuring test strip prescriptions delivered by pharmacies from the province of Buenos Aires (8115 records collected during 3 months provided by the Colegio de Farmacéuticos de la Provincia de Buenos Aires) of affiliates with type 2 diabetes (T2DM) from 2 large entities of the SSS system. The average monthly test strips/patient used for SMBG was 97.5 ± 70.1. This number varied according to treatment: monotherapy with oral antidiabetic drugs (OAD) < combined OAD therapy < insulin treatment. Test strips represented a higher percentage of the total prescription cost in people under OAD monotherapy (84.6%) and lower in those with insulin analogs (46.9%). In our population, the type of hyperglycemia treatment was the main driver of test strip use for SMBG and its impact on the total prescription cost depends on the kind of such treatment. Since it has been shown that patients' education and prescription audit can optimize test strip use and treatment outcomes, implementation of such strategies could appropriately support, optimize, and reduce ineffective test strip use in people with T2DM.

Evaluación económica del tratamiento de diabetes tipo 2 con saxagliptina en Colombia / Economic evaluation of type 2 diabetes treatment with saxagliptin in Colombia

Objetivo: Determinar la relación costo efectividad incremental del agregado de saxagliptina o sulfonilureas en Colombia a personas con DMT2 que no logran alcanzar metas glucémicas con metformina, durante un período máximo de 20 años. Metodología: Se realizó un estudio de costo efectividad, utilizando un modelo de simulación de eventos discretos con incremento de tiempo fijo (Diabetes Cardiff Model). Las características de la cohorte de pacientes y el perfil de eficacia para cada tratamiento se obtuvieron de la literatura. El costo de los medicamentos se obtuvo de SISMED y Farmaprecios. Los costos de los eventos macro y microvasculares se basaron en el POS, Manual Tarifario SOAT y consulta con experto local. La tasa de descuento en costos y beneficios fue 3,5 por ciento. Resultados: En el grupo tratado con saxagliptina registramos menos eventos fatales y no fatales y menos episodios de hipoglucemia. En ambas estrategias los mayores costos correspondieron a los medicamentos, seguidos por los asociados al tratamiento del infarto de miocardio. El costo incremental de la terapia con saxagliptina fue de US$ 555.552 a 20 años. El tratamiento con saxagliptina redundó en un mayor número de Años de Vida Ajustados por Calidad (AVAC) y Años de Vida Ganados (AVG), respecto al obtenido con sulfonilureas. El costo por AVAC fue de US$ 2.190. Los resultados de costo efectividad fueron robustos al análisis de sensibilidad. Conclusión: El agregado de saxagliptina a pacientes que no logran un control glucémico adecuado con metformina, es muy costo efectiva comparada con el agregado de sulfonilureas.

Objective: To determine in Colombia, the cost effectiveness ratio of the saxagliptin or sulphonylureas addition to patients with T2DM who fail to achieve glycemic goals with metformin, for a maximum period of 20 years. Methods: We performed a cost effectiveness analysis, using a discrete event simulation model with fixed time step (Cardiff Diabetes Model). The characteristics of the cohort of patients and efficacy profile for each treatment were obtained from the literature. The cost of medication was obtained from SISMED and Farmaprecios. The costs of macro and microvascular events were based on POS tariffs, SOAT Manual and consultation with local expert. The discount rate on costs and benefits was 3.5 percent. Results: The group treated with saxagliptin had fewer fatal and nonfatal events and fewer episodes of hypoglycemia than the one with sulfonylureas. In both strategies the higher cost corresponds to the drugs, followed by those associated with the treatment of myocardial infarction. The incremental cost of saxagliptin therapy was US$ 555.552 to 20 years. Saxagliptin treatment resulted in a greater number of quality-adjusted life year (QALYs) and life-years gained (LYG) than that obtained with sulfonylureas. The cost per QALY was US$ 2,190. Cost-effectiveness results were robust to sensitivity analysis. Conclusion: Addition of saxagliptin to patients who do not achieve adequate glycemic control with metformin, is highly cost-effective compared with the addition of sulphonylureas.

Diabetes control- the legacy of a memory

Achieving and maintaining good glycaemic control remains an important goal in the management of this common and prevalent disorder. Recent evidence from important megatrials, ACCORD, ADVANCE, VADT, UKPDS-10 year follow-up as well as the STENO-2 follow-up study, have cleared doubts concerning the benefits of targeting good glycaemic control. For the first time, we have the reassurance that macrovascular benefits can be realised from good glycaemic control. The legacy effect of prior good glucose control from the UKPDS-10 year follow-up, reinforces the results seen from the DCCT-EDIC (for Type 1 diabetes). The Intervention Phase of the UKPDS revealed benefits for reduction of microvascular complications, while it was only at the end of the Post-Trial Monitoring Phase where significant improvements in both micro and macrovascular outcomes were seen. The other three Trials assessing the effect of glycaemic control on cardiovascular outcomes, although largely negative for CV benefit, give valuable insight towards appropriate patient characteristics for which aggressive glucose control can and should be instituted. Individualising glycaemic targets, which has been the approach that many clinicians have been practising, has received new impetus albeit with clearer details. Getting to glycaemic goal early in the course of T2DM and Doing to Safely (Avoiding hypoglycaemia) are the key ingredients to successful management. The legacy of the memory of initial good metabolic/glycaemic control is investment in good health with benefits of reductions in both micro and more importantly, macrovascular disease, years later. Multifactorial interventions that include blood pressure, lipid lowering in addition to glucose control in these individuals with the Metabolic Syndrome result in more immediate beneficial additive effects on cardiovascular outcomes.